title: Presenilin influences glycogen synthase kinase-3 β (GSK-3β) for kinesin-1 and dynein function during axonal transport.
abstract: Within axons, molecular motors transport essential components required for neuronal growth and viability. Although many levels of control and regulation must exist for proper anterograde and retrograde transport of vital proteins, little is known about these mechanisms. We previously showed that presenilin (PS), a gene involved in Alzheimer's disease (AD), influences kinesin-1 and dynein function in vivo. Here, we show that these PS-mediated effects on motor protein function are via a pathway that involves glycogen synthase kinase-3β (GSK-3β). PS genetically interacts with GSK-3β in an activity-dependent manner. Excess of active GSK-3β perturbed axonal transport by causing axonal blockages, which were enhanced by reduction of kinesin-1 or dynein. These GSK-3β-mediated axonal defects do not appear to be caused by disruptions or alterations in microtubules (MTs). Excess of non-functional GSK-3β did not affect axonal transport. Strikingly, GSK-3β-activity-dependent axonal transport defects were enhanced by reduction of PS. Collectively, our findings suggest that PS and GSK-3β are required for normal motor protein function. Our observations propose a model, in which PS likely plays a role in regulating GSK-3β activity during transport. These findings have important implications for our understanding of the complex regulatory machinery that must exist in vivo and how this system is coordinated during the motility of vesicles within axons.
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY 14260, USA.
authors.forename: Kunsang
authors.initials: K
authors.lastname: Dolma
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Iacobucci
authors.forename: Kan
authors.initials: K
authors.lastname: Hong Zheng
authors.forename: Jayasha
authors.initials: J
authors.lastname: Shandilya
authors.forename: Eneda
authors.initials: E
authors.lastname: Toska
authors.forename: Joseph A
authors.initials: JA
authors.lastname: White
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spina
authors.forename: Shermali
authors.initials: S
authors.lastname: Gunawardena
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000502:physiology*; D002460:Cell Line; D004330:Drosophila; D004398:Dyneins / Q000378:metabolism*; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000235:genetics; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053763:Presenilins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D004398:Dyneins; D016547:Kinesins